NEW YORK (Reuters Health) - Diabetes medications have varying impacts on the risk for hepatocellular cancer (HCC), a new meta-analysis confirms.

Metformin seems to be substantially protective whereas insulin and other drugs that work along the insulin pathway may increase the risk, Dr. William Sanchez and colleagues from the Mayo Clinic, Rochester, Minnesota, reported February 5 in the American Journal of Gastroenterology.

"The context that makes this important," Dr. Sanchez noted in an interview, is that the rates of diabetes and obesity are rising and "in addition to being a big cause of heart disease, these disorders are also a big cause of liver disease, which some people don't tend to appreciate."

Several preclinical and observational studies have suggested that conventional diabetes medications may modify the risk of HCC. To better understand these associations, the Mayo Clinic team performed a systematic review and meta-analysis of 10 studies reporting 22,650 cases of HCC in 334,307 patients with type 2 diabetes. There were five case-control studies, three cohort studies and two randomized controlled trials (RCTs).

Relative to non-use, use of metformin was associated with a 50% reduction in risk of developing HCC (odds ratio 0.50). In contrast, use of a sulfonylurea was associated with a 62% increase in HCC incidence (OR 1.62) and use of insulin with a 161% increase in risk (OR 2.61).

"Laboratory studies suggest that insulin and insulin-like agents promote insulin-like growth hormones that might drive cancer so there is a biochemical reason to think this may be so," Dr. Sanchez told Reuters Health.

Use of thiazolidinediones did not appreciably modify the risk of HCC.

The researchers say the effects they observed were stable across both case-control and cohort studies, persisted after adjusting for the concomitant effect of other anti-diabetes medications, and were more pronounced in the Western population, as compared to the Asian population, where the incidence of diabetes, obesity, and non-alcoholic fatty liver disease is rapidly rising.

The analysis was limited by considerable heterogeneity across studies, they note. And the studies did not adjust for the same confounders and they generally failed to account for one of the following risk factors for HCC: cirrhosis, viral hepatitis, alcoholic liver disease, metabolic syndrome or treatment for hepatitis B and/or hepatitis C.

One "major omission" of all the studies was failure to adjust for statin therapy. "What we don't know from the current analysis," Dr. Sanchez said, "is whether the protective effect comes from metformin or something else, like statins. However, odds are that a lot of these patients who are diabetic are going to be on a statin. The likelihood is that the use of statins is similar across the groups, but we don't know for sure." Dr. Sanchez also said that in a recent meta-analysis by him and his colleagues, statins did have a protective effect against HCC.